scholarly journals Clofibrate Treatment Decreases Inflammation and Reverses Myocardial Infarction-Induced Remodelation in a Rodent Experimental Model

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 270 ◽  
Author(s):  
Luz Ibarra-Lara ◽  
María Sánchez-Aguilar ◽  
Elizabeth Soria-Castro ◽  
Jesús Vargas-Barrón ◽  
Francisco Roldán ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Cardiac Damage ◽  
Artery Ligation ◽  
Apoptotic Proteins

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments have failed to reverse ischemic-induced cardiac damage. Therefore, our aim was to study if clofibrate treatment was capable of decreasing inflammation and apoptosis, and reverse ventricular remodeling and MI-induced functional damage. Male Wistar rats were assigned to (1) Sham coronary artery ligation (Sham) or (2) Coronary artery ligation (MI). Seven days post-MI, animals were further divided to receive vehicle (V) or clofibrate (100 mg/kg, C) for 7 days. The expression of IL-6, TNF-α, and inflammatory related molecules ICAM-1, VCAM-1, MMP-2 and -9, nuclear NF-kB, and iNOS, were elevated in MI-V. These inflammatory biomarkers decreased in MI-C. Also, apoptotic proteins (Bax and pBad) were elevated in MI-V, while clofibrate augmented anti-apoptotic proteins (Bcl-2 and 14-3-3ε). Clofibrate also protected MI-induced changes in ultra-structure. The ex vivo evaluation of myocardial functioning showed that left ventricular pressure and mechanical work decreased in infarcted rats; clofibrate treatment raised those parameters to control values. Echocardiogram showed that clofibrate partially reduced LV dilation. In conclusion, clofibrate decreases cardiac remodeling, decreases inflammatory molecules, and partly preserves myocardial diameters.

Blockade of AT1 receptors and Na+/H+exchanger and LV dysfunction after myocardial infarction in rats

1999 ◽  
Vol 277 (2) ◽  
pp. H610-H616 ◽  
Author(s):  
Marcel Ruzicka ◽  
Baoxue Yuan ◽  
Frans H. H. Leenen
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Ang Ii ◽  
Artery Ligation ◽  
Volume Load ◽  
Lv Dysfunction

Mechanical stretch, ANG II, and α1-receptor stimulation may contribute to cardiac remodeling after myocardial infarction (MI). Each of these mechanisms involves different signaling pathways for the cellular hypertrophic response. All three also activate the Na+/H+exchanger. In the present study we evaluated the hypothesis that activation of the Na+/H+exchanger is involved in parallel with other signaling mechanisms for ANG II. Three days before coronary artery ligation, rats were randomly allocated to no treatment or treatment with amiloride, losartan, or amiloride and losartan in combination. Four weeks after coronary artery ligation, left ventricular (LV) function was assessed from in vivo resting cardiac pressures, hemodynamic responses to cardiac volume and pressure load, and cardiac remodeling by in vitro pressure-volume curves and LV and right ventricle (RV) weight. Amiloride and losartan given alone to a similar extent attenuated the shift of the pressure-volume curve to the right. This effect was significantly more pronounced with amiloride and losartan in combination. Each drug alone to a minor extent improved LV responses to pressure and volume load. However, with amiloride and losartan in combination, close-to-normal responses to pressure and volume load were observed. Losartan and amiloride alone had only a small effect on development of RV hypertrophy after MI but in combination completely prevented the RV hypertrophy. Amiloride and losartan appear to be complementary in prevention of cardiac remodeling and LV dysfunction after MI. This finding suggests that, besides ANG II, other mechanisms activating the Na+/H+exchanger contribute to cardiac remodeling after MI.

Comparison of Myocardial Infarction with Sequential Ligation of the Left Anterior Descending Artery and Its Diagonal Branch in Dogs and Sheep

2003 ◽  
Vol 26 (4) ◽  
pp. 351-357 ◽  
Author(s):  
W.G. Kim ◽  
Y.C. Shin ◽  
S.W. Hwang ◽  
C. Lee ◽  
C.Y. Na
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Pulmonary Artery ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Suitable Model ◽  
Artery Ligation ◽  
Diagonal Branch ◽  
Left Anterior Descending Artery ◽  
Arterial Blood

We report a comparison of the effects of myocardial infarction in dogs and sheep using sequential ligation of the left anterior descending artery (LAD) and its diagonal branch (DA), with hemodynamic, ultrasonographic and pathological evaluations. Five animals were used in each group. After surgical preparation, the LAD was ligated at a point approximately 40% of the distance from the apex to the base of the heart, and after one hour, the DA was ligated at the same level. Hemodynamic and ultrasonographic measurements were performed preligation, 30 minutes after LAD ligation, and 1 hour after DA ligation. As a control, two animals in each group were used for the simultaneous ligation of the LAD and the DA. Two months after the coronary ligation, the animals were evaluated as previously, and killed for postmortem examination of their hearts. All seven animals in the dog group survived the experimental procedures, while in the sheep group only animals with sequential ligation of the LAD and DA survived. Statistically significant decreases in systemic arterial blood pressure and cardiac output, and an increase in the pulmonary artery capillary wedge pressure (PACWP) were observed one hour after sequential ligation of the LAD and its DA in the sheep, while only systemic arterial pressures decreased in the dog. Ultrasonographic analyses demonstrated variable degrees of anteroseptal dyskinesia and akinesia in all sheep, but in no dogs. Data two months after coronary artery ligation showed significant increases in central venous pressure, pulmonary artery pressure, and PACWP in the sheep, but not in the dog. Left ventricular end-diastolic dimension and left ventricular end-systolic dimension in ultrasonographic studies were also increased only in the sheep. Pathologically, the well-demarcated thin-walled transmural anteroseptal infarcts with chamber enlargement were clearly seen in all specimens of sheep, and only-mild-to-moderate chamber enlargements with endocardial fibrosis were observed in the dog hearts. In conclusion, this study confirms that the dog is not a suitable model for myocardial infarction with failure by coronary artery ligation despite negligent operative mortality, when compared directly with an ovine model.

scholarly journals Progression of heart failure after myocardial infarction in the rat

2001 ◽  
Vol 281 (5) ◽  
pp. R1734-R1745 ◽  
Author(s):  
J. Francis ◽  
R. M. Weiss ◽  
S. G. Wei ◽  
A. K. Johnson ◽  
R. B. Felder
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Left Ventricular Remodeling ◽  
Plasma Renin ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple “switching on” of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.

Abstract 15058: Disruption of Extracellular Cytotoxic Chromatin by Acute DNase1 Administration Improves Left Ventricular Remodeling after Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Benjamin Vogel ◽  
Hisahito Shinagawa ◽  
Ullrich Hofmann ◽  
Georg Ertl ◽  
Stefan Frantz
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Pcr Analysis ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Artery Ligation ◽  
High Concentrations

Rationale: Myocardial infarction (MI) leads to necrosis of multinucleated and polyploid myocytes. This causes uncontrolled release of cellular content like chromatin to the infarct area. Chromatin is mainly comprised of histones which are essential for controlling and packing of DNA but paradoxically are also known to be cytotoxic. This makes free chromatin a toxic DNA polymer creating local high concentrations of hazardous histones. Objective: We hypothesized that chromatin from necrotic cells accumulates in ischemic myocardium, creates local high concentrations of cytotoxic histones, and thereby potentiates ischemic damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion and could decrease local histone concentrations and cytotoxicity. Methods and Results: After permanent coronary artery ligation in mice we found extracellular histones accumulated within the infarcted myocardium. Histone cytotoxicity towards isolated myocytes was confirmed in vitro. To reduce histone related cytotoxicity in vivo DNase1 was injected within the first 6 hours after induction of MI. DNase1 accumulated in the infarcted region of the heart, effectively disrupted extracellular cytotoxic chromatin and thereby reduced high local histone concentration. Animals acutely treated with DNase1 revealed significantly improved left ventricular remodeling as measured by serial echocardiography up to 28 days after MI (e.g. NaCl vs DNase1, papillary end diastolic area [mm 2 ]: 23.26 ± 2.06 vs 18.90 ± 1.24, n=9 vs 10, p<0,05). Treatment did not influence mortality, infarct size or inflammatory parameters as determined by neutrophil infiltration and RTQ-PCR analysis of characteristic cytokines. However improved myocyte survival was discovered within the infarct region which might account for the protective effects in DNase1 treated animals (NaCl vs DNase1: 3.0 ± 0.7% vs 8.3 ± 2.3%; p<0.05; n=7 vs 8). Conclusions: Targeting extracellular cytotoxic chromatin within the infarcted heart by DNase1 is a promising approach to preserve myocytes from histone induced cell death and to conserve left ventricular function after MI. The efficacy of other chromatin degrading agents is now under investigation.

Depletion of cardiac 14-3-3η protein adversely influences pathologic cardiac remodeling during myocardial infarction after coronary artery ligation in mice

2016 ◽  
Vol 202 ◽  
pp. 146-153 ◽  
Author(s):  
Remya Sreedhar ◽  
Somasundaram Arumugam ◽  
Rajarajan A. Thandavarayan ◽  
Vijayasree V. Giridharan ◽  
Vengadeshprabhu Karuppagounder ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Cardiac Remodeling ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Cardioprotective Effect of Polydatin on Ventricular Remodeling after Myocardial Infarction in Coronary Artery Ligation Rats

Planta Medica ◽  
2015 ◽  
Vol 81 (07) ◽  
pp. 568-577 ◽  
Author(s):  
Yan Gao ◽  
Jianping Gao ◽  
Changxun Chen ◽  
Huilin Wang ◽  
Juan Guo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Ventricular Remodeling ◽  
Cardioprotective Effect ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction

2010 ◽  
Vol 298 (5) ◽  
pp. H1415-H1425 ◽  
Author(s):  
Sih Min Tan ◽  
Yuan Zhang ◽  
Kim A. Connelly ◽  
Richard E. Gilbert ◽  
Darren J. Kelly
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Type I ◽  
Artery Ligation ◽  
Receptor Like Kinase

Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-β signaling using a novel orally active TGF-β type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 mg·kg−1·day−1 or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 ( P < 0.01), α-smooth muscle actin ( P < 0.001), and collagen I ( P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition ( P < 0.05). In brief, treatment with a novel TGF-β type I receptor inhibitor, GW788388, significantly reduced TGF-β activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.

Abstract 3659: High-Mobility Group Box 1 Restores Cardiac Dysfunction after Myocardial Infarction in Transgenic Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tatsuro Kitahara ◽  
Yasuchika Takeishi ◽  
Tetsuro Shishido ◽  
Satoshi Suzuki ◽  
Shigehiko Kato ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Cardiac Dysfunction ◽  
Nuclear Dna ◽  
Inflammatory Responses ◽  
High Mobility ◽  
Left Ventricular ◽  
High Mobility Group ◽  
Coronary Artery Ligation ◽  
Artery Ligation

High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein and is released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. To test the hypothesis that HMGB1 enhances angiogenesis and restores cardiac dysfunction after myocardial infarction, we generated transgenic mouse with cardiac specific overexpression of HMGB1 (HMGB1-Tg) using α-myosin heavy chain (MHC) promoter. The left anterior descending coronary artery was ligated in HMGB1-Tg and wild-type littermate (Wt) mice. After coronary artery ligation, HMGB1 was released into circulation from the necrotic cardiomyocytes of HMGB1 overexpressing hearts. The size of myocardial infarction was smaller in HMGB1-Tg than in Wt mice (figure ). Echocardiography and cardiac catheterization demonstrated that cardiac remodeling and dysfunction after myocardial infarction were prevented in HMGB1-Tg mice compared to Wt mice. Furthermore, survival rate after myocardial infarction in HMGB1-Tg mice was higher than that in Wt mice (figure ). Immunohistochemical staining revealed that capillary and arteriole formations after myocardial infarction were enhanced in HMGB1-Tg mice. We demonstrated the first in vivo evidence that HMGB1 enhances angiogenesis, restores cardiac dysfunction, and improves survival after myocardial infarction. These results may provide a novel therapeutic approach for left ventricular dysfunction after myocardial infarction.

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